DE4107152C2 - Preparations for non-invasive administration of antidiabetics - Google Patents

Description

The invention relates to preparations for non-invasive Administration of anti-diabetic agents, especially of Insulin, in the form of liposome-like, the active ingredient containing droplets from in a membrane-like envelope amphiphilic substance enclosed hydrophilic liquid, and a process for their production.

Efforts to bring anti-diabetic substances into the body, already exist without using the usual injection needle long (see e.g. the overview by Lassmann-Vague (Diabete. Metab. 14, 728, 1988). So z. B. suggested implantable storage containers (Wang, P. Y, Biomaterials 10, 197, 1989) or pumps (Walter, H et al., Klin. Wochenschr. 67, 583, 1989) to use an insulin solution transnasally (Mishima et al., J. Pharmacobio.-Dynam. 12, 31, 1989), perocular (Chiou et al., J. Ocul. Pharmacol. 5, 81, 1989), orally in a liposome suspension (Rowland & Woodley,  Biosc. Rep. 1, 345, 1981) or to apply transrectally; when the insulin molecules are inserted through the skin should, the agent solution z. B. transcutaneously Jet Injection (Siddiqui & Chien, Crit. Rev. Ther. Drug. Carrier. Syst. 3, 195, 1987), using small injectors (Fisken, Lancet 1, 787, 1989), of electric fields (Burnette & Ongpipattanakul, J. Pharm. Sci. 76, 765, 1987; Meyer, B.R. et al., Amer. J. Med. Sci. 297, 321, 1989) or supported by chemical additives permeationally.

However, all of these procedures have hardly any relief for brought to the diabetic - maybe with the exception of Jet injection, which is however only a refined, technically very elaborate form of injection is and therefore not widely used. The everyday life of every insulin dependent patient includes continue to inject an insulin solution daily the skin or into the muscle tissue (De Meÿer, P. et al., Neth. J. Med. 34, 210, 1989).

Lipids have been delayed as excipients for the Release of insulin implants discussed (Wang, P. Y Int. J. Pharm. 54, 223, 1989) or, in the form of liposomes, as Vehicle for oral administration proposed (Patel, Biochem. Soc. Transast. 13, 513, 1985), but without the results being reproducible (Das, N. et al., Biochem. Int. 16, 983, 1988). Further work in the field of the insulin-containing liposomes dealt with methodological, non-therapeutic questions (Wiessner, J. H. and Hwang, K. J. Biochim. Biophys. Acta 689, 490, 1982; Sarrach, D. Stud. Biophys. 100, 95, 1984; Sarrach, D. and Lachmann, U. Pharmazie 40, 642, 1985; Weingarten, C. et al. Int. J. Pharm. 26, 251, 1985; Sammins, M.C. et al., J. Pharm. Sci. 75, 838, 1986; Cervato, G. et al., Chem. Phys. Lipids 43, 135, 1987).  

DE-OS 30 16 976 describes liposomes with a wall membrane based on phospholipids, in the molecules of a non-amphiphi len, oily substance (such as mineral oils, waxes or triglyce ride) are known. The oily substance is said to be a stabilizer Lipization of the liposome membrane cause, which requires a entire release of in the exclusively by injection applied active ingredients containing liposomes is achieved.

DE-OS 37 13 494 describes a dispersion of liposomes, whose wall membrane made of a lipid amphiphile, which additionally contains up to 50% by weight of a cholesterol sulfate salt, is formed, and a method for producing them Dispersion described. The dispersed liposomes can superficial application to the skin active ingredients in the skin transport, however, are not explicit for the transport of antidiabetic drugs suitable through the skin.

It is therefore an object of the invention to prepare preparations for non-invasive administration of anti-diabetic agents, especially of insulin, to create an improved, therapeutically sufficient and reproducible Enable drug application.

Another object of the invention is to provide a To provide processes for the preparation of such preparations.

The features of the independent serve to solve this task Claims.

Advantageous embodiments are in the subclaims Are defined.

It was surprisingly found that by using novel drug carriers, here as transfersomes referred to anti-diabetes medication without syringes or Accompanying measures introduced through the skin into the blood can be. So achieve z. B. regularly more than 50%, often more than 90% of those applied percutaneously Insulin molecules find their destination in the body when they do were attached by means of transfersomes. Insulin-containing Transfersomes that can be applied to the skin consequently successfully injecting insulin solutions replace.

Through this invention, a way was thus found for simple, non-invasive and completely painless therapy Type II Diabetes: Transfersomes can be used alone or in Combination with any dosing device for problem-free acute and / or chronic diabetes treatment used become.  

The transferomes used according to the invention are known Similar to liposomes. Like these, they include (at least) one amphiphilic substance, especially a lipid, with water and other polar hydrophilic substances vesicle structures can train. There is a microscopic droplet in them hydrophilic liquid from at least one shell amphiphilic substance enclosed, the diameter of the Total transfersomes of the order of less than is a tenth of a µm to a few µm, but smaller carriers priority is often given. Usually it becomes very much greater permeability of transfersomes (im Comparison with known liposomes) by edge-active substances reached. More details can be found in the Patent application P 41 07 153.0-41 with the title "Preparation for drug application in the smallest droplet form" described, the content of which is hereby expressly stated in the Disclosure content of this application is included.

Critical for the permeation properties of the invention Transfersomes is their elasticity without significant ones Impairment of overall stability is much greater than known, similar liposomes.

This greater elasticity (and thus permeability) is achieved for example and preferably in that the Transfersomes are given a content of marginally active substance, which is an optimal approach to the solubilization limit causes d. H. a content of marginally active substance that the Would destabilize droplets.

At least one amphiphilic substance is advantageous physiologically acceptable polar or non-polar lipid or another pharmacologically acceptable amphiphilic Substance; the suitable molecules are characterized by  that they form stable drug-bearing aggregates. The preferred form of aggregate are lipid vesicles, the preferred Membrane structure is a double layer.

It is also advantageously provided that at least one such Substance a lipid or lipoid from a biological source or is a corresponding synthetic lipid, or Modification of such lipids, for example a glyceride, Glycerophospholipid, sphingolipid, isoprenoid lipid, steroid, Sterol or sterol, a sulfur or carbohydrate-containing one Lipid, or any other lipid that is stable Forms double layers, e.g. B. a semi-protonated fluid Fatty acid. So lipids are made from egg, soybean, coconut, Olives, safflower, sunflowers, linseed, whale fat, evening primrose or primrose used, with natural or, partially or fully hydrogenated (hardened), or exchanged chains. They find it particularly often corresponding phosphatidylcholine application; but also Phosphatidylethanolamines, phosphatidylglycerols, Phosphatidylinositols, phosphatidic acids and Phosphatidylserines, as well as Sphingomyeline or Sphingophospholipids, glycosphingolipids (e.g. cerebroside, Ceramide polyhexosides, sulfatides, sphingoplasma malogens), Gangliosides or other glycolipids are for use in Well suited for the purposes of this invention. Of synthetic lipids the corresponding dioleoyl, Dilinoleyl, dilinolenyl, dilinolenoyl, diaracidonyl, Dimyristoyl, more rarely dipalmitoyl, distearoyl, phospholipids or the corresponding sphingosine derivatives, Glycolipids or other diacyl or dialkyl lipids used; also any combinations of the mentioned Substances are suitable.  

The edge-active substance is advantageously a nonionic, a zwitterionic, an anionic or a cationic Surfactant. It can contain an alcohol residue. Be happy long chain fatty acids or fatty alcohols, alkyl trimethyl ammonium salts, alkyl sulfate salts, cholate, deoxycholate, Glycodeoxycholate, taurodeoxycholate salts, dodecyl dimethyl amine oxide, decanoyl- or dodecanoyl-N-methylglucamide, N-dodecyl-N, N-dimethylglycine, 3- (Hexadecyldimethylammonio) propane sulfonate, N-hexadecyl sulfobetaine, non-ethylene glycol octylphenyl ether, non-ethylene dodecyl ether, octaethylene glycol isotridecyl ether, Octaethylene dodecyl ether, polyethylene glycol 20 sorbitan Monolaurate, polyethylene glycol 20 sorbitan Monooleate, polyhydroxyethylene cetylstearyl ether, Polyhydroxyethylene-4-lauryl ether, Polyhydroxyethylene-23 lauryl ether, Polyhydroxyethylene-8-stearate, Polyhydroxyethylene 40 stearate, Polyhydroxyethylene 100 stearate, polyethoxylated Castor oil 40, polyethoxylated hydrogenated Castor oil, sorbitan monolaurate, particularly preferably decanoyl- or dodecanoyl-N- methylglycamide, lauryl or oleoyl sulfate salts, Sodium deoxycholate, sodium glycodeoxycholate, sodium oleate, Sodium elaidate, sodium linoleate, sodium laurate, non-ethylene dodecyl ether, polyethylene glycol 20 sorbitan monooleate, Polyhydroxyethylene-23 lauryl ether, Polyhydroxyethylene 40 stearate, sorbitan monolaurate, etc. used.

The most suitable surfactants in these classes of substances include: n-tetradecyl (= myristoyl) glycerophosphatidic acid, n-hexadecyl (= Palmityl) -glycerophosphatidic acid, n-octadecyl (= stearyl) - glycerophosphatidic acid, n-hexadecylene (= palmitoleil) glycero-  phosphatidic acid, n-octadecylene (= oleil) glycero- phosphatidic acid, n-tetradecyl-glycerophosphoglycerol, n- Hexadecyl-glycerophosphoglycerol, -n-octadecyl-glycero- phosphoglycerol, n-hexadecylene-glycerophosphoglycerol, n- Octadecylene-glycerophosphoglycerol, n-tetradecyl-glycerol phosphoserine, n-hexadecyl-glycerophosphoserine, -n-octadecyl- glycerophosphoserine, n-hexadecylene glycerophosphoserine and n-octadecylene glycerophosphoserine.

The total concentration of amphiphilic substance in the preparation is expedient 0.1 to 30% by weight. This concentration is preferably between 0.1 and 15%, particularly often between 5 and 10%.

The total amount of non-active substance in the system is conveniently 0.1% to 99 mol% of the amount for a Solubilization of the droplets would be required. This is often the case Optimal depending on the active ingredient in a range between 1 and 80 mol%, preferably between 10 and 60 mol%; especially values between 20 and 50 mol% are preferred.

The active substance concentration for insulin is usually 1 up to 500 I.U./ml; the concentration is preferably below this between 20 and 100 I.U./ml. The concentration of the amphiphilic substance lies then preferably in the range of 0.1-20% by weight, often between 0.5 and 15 wt .-%, particularly often between 2.5 and 10% by weight.

For the manufacture, the amphiphilic substances, in particular Lipids, either as such or dissolved in a physiological compatible, water-miscible solvent or Solution mediator combined with a polar solution and so the formation of droplets is initiated.  

It is advantageous that the polar solution is the marginally active Contains substances. These can also be found in the lipids or their solution may be included.

The droplet formation is preferably by stirring in by means of Evaporation from a reverse phase, through an injection or Dialysis, by mechanical action, e.g. B. by Shake, stir, homogenize, sonicate, rub, Freeze or thaw through high and low pressure Filtration or other energy supply brought about.

It can be advantageous if the active ingredient inclusion after Droplet formation occurs.

In the manufacture of transfersomes by filtration preferred that the filter material have a pore size of 0.1-0.8 microns, especially 0.15-0.3, and particularly preferred 0.22 microns, with multiple filters in a row can be used.

In the case of transfersome production using ultrasound energy densities of 10-50 kW / liter / minute are preferred used; in mechanical agitators such. B. typically Rotation ranges from 1000 to 5000 per minute for the Production of transfersomes well suited: in High pressure homogenizers ensure pressures of 300-900 bar sufficient passage homogeneity after a passage and -Quality, including suspensions with 20-30% lipid can be edited easily.

It is often convenient to transferoms just before the Make application from a concentrate or lyophilisate.  

Cryopreservatives, such as B. oligosaccharides, facilitate the transferome formation from the lyophylisate.

Usual active ingredients, auxiliaries or additives, preferably Stabilizers, preservatives, consistency formers, or Markers can be used in the context of the invention.

The following examples illustrate the invention without restrict them. Temperatures are in degrees Celsius, Carrier sizes in nanometers, and other sizes in the usual SI Units specified.

example 1 composition

386 mg soybean phosphatidylcholine (purer than 95%)
58.5 mg sodium cholate (L / D = 3.5)
500 µl ethanol (96%)
2.25 ml 0.9% NaCl solution (per injection)
2.25 ml Actrapid HM 40 (corresponds to 90 IU recombinant human insulin)

Manufacturing

The lipid is dissolved in the heated ethanol, then the Na Cholat dissolved in this solution.

A mixture of the aqueous solution is added to the alcoholic solution  Saline with the human, recombinant insulin (with 6.75 mg m-cresol) added. There is a cloudy Suspension that is aged overnight. After 12 hours this suspension using nitrogen gas at a pressure of 0.25 MPa under sterile conditions through a sterile filter (Anodisc, pore diameter 0.2 µm) and then packed.

The nominal lipid / cholate ratio is 3.5 / 1 calculated molar cholate concentration in the Lipid bilayer corresponds to a ratio of 3/1. The corresponds to an estimated 50% of the solubilization concentrations tration.

The mean vesicle radius of the finished suspension in this Preparation, determined by means of dynamic light scattering, is 97 nm.

application

400 µl of the fresh, insulin-containing transfersome vesicle suspension are applied to the untreated skin on the left forearm of an informed, voluntary, healthy, male test subject (37 years) who has been sober for 18 hours and distributed over approx. 10 cm ² . 5 minutes later, another 200 µl of the same suspension, one half each, is placed on the forearm and upper arm. This corresponds to a total of 12 IU insulin. 5-10 minutes later, the suspension on the upper arm (dose approx. 2.5 mg / cm ² ) is no longer visible, that is, it has completely penetrated, while lipid residues can still be observed on the forearm (dose approx. 7.5 mg / cm ² ) .

effect

To record the insulin effect, an iv catheter is positioned on the right wrist approx. 2 hours before the sample is applied. At intervals of 15-45 minutes, 1-1.5 ml of blood are drawn; the first 0.5-1 ml are discarded and the remaining 0.5 ml used for an enzymatic glucose test. Three measurements of four independent samples are carried out. The measurement results are shown in Fig. 1. They show that a significant drop in blood glucose occurs about 90 minutes after application by means of transfersome vesicles, which lasts about 2 hours and is about 50% of the height and 200% of the duration of a comparable subcutaneous insulin application.

Example 2 composition

120 mg soybean phosphatidylcholine (purer than 95%)
20 mg sodium cholate pa (L / D = 3.2)
150 µl ethanol (96%)
1.45 ml Actrapid HM 100 (recombinant human insulin 100 IU / ml)

Manufacturing

The production takes place with small modifications as in Example 1 described. The difference is that Lipid / insulin mixture just a few minutes after Preparation using a 1 ml disposable syringe through a 0.22 µm polycarbonate filter (Sartorius) is hand filtered. The  Final volume of the suspension is 1.2 ml; the lipid / cholate ratio is nominally 2.8 / 1, in the membrane approx. 2.4 / 1. The Final insulin concentration equals 83 I.U./ml; the Vesicle radius is one day after preparation in the Average 94 nm; a week later 170 nm.

application

One and a half hours after the start of the test, 240 μl of the fresh, sterile suspension of insulin-containing transferomes are removed (20 IU). These are applied to the inner surface of the right forearm of a male subject who has been sober for 18 hours and evenly distributed at approx. 0.7 mg / cm ² . 5 minutes later the skin is macroscopically dry; 45 minutes later there is no trace of the order.

effect

Through an i. v. Catheters in the left forearm are in irregular intervals every 15 to 40 minutes Blood samples taken. The blood glucose determination is carried out as in Example 1 described.

The time course of transferoma-related hypoglycemia is shown in Fig. 2. The blood glucose level drops by 10 mg / ml after an hour and a half; This artificial hypoglycemia lasts for at least 4 hours and thus reaches 70-80% of the value achieved by conventional subcutaneous insulin application with the drug Actrapid. The control results obtained with such a sc insulin application (from transfersomes) are shown as crosses in this picture; the overall effect corresponds to that expected for the free substance.

Example 3 composition

216 mg phosphatidylcholine from soybeans (487 µl of a 50% solution in absolute ethanol)
27 mg egg phosphatidylglycerol (98%)
29.45 mg oleic acid, puriss.
3 ml Actrapid HM 100 (recombinant human insulin 100 IU / ml)
40 µl 1 N NaOH
20 µl 1 N NaCl

Manufacturing

The lipids are mixed until the solution appears clear. After the addition of Actrapid solution, lye and saline a cloudy suspension is formed. After pressing this Suspension through a polycarbonate filter with pore diameter of 0.2 µm creates a slightly opalescent suspension. This consists of vesicles (transfersomes) with a medium one Diameter of 320 nm.

application

The initial concentration of glucose in the blood of a subject (70 kg, 37 years, normoglycemic, 24 hours fasting) is measured over 90 minutes as a reference. Then the transfersome suspension described above with a nominal 85 IU insulin / ml, which was stored for 12 hours at 4 ° C., is applied to the right forearm (approx. 330 μl per 15 cm ² ); this corresponds to an order of 28 IU

effect

The blood samples are taken from a vein on the left forearm via a heparinized permanent catheter; 0.5 ml of each sample is sedimented and frozen immediately; the remaining volume is used to determine the glucose concentration enzymatically. This concentration drops by approximately 8 mg / dl after approx. 2.5 hours and remains reduced over 4.4 hours. This corresponds to 75% of the maximum achievable effect caused by a sc injection in the control test. The pharmacokinetics of this test series is presented in Fig. 3.

Fig. 4 summarizes the results of three exemplary percutaneous insulin applications with transfersomes and two sc injections.

Example 4 composition

143 mg soybean phosphatidylcholine
18 mg egg phosphatidylglycerol (98%)
19.6 mg oleic acid, puriss.
2 ml Actrapid HM 100 (200 IU)
25 µl 1 N NaOH

Manufacturing

The lipids are weighed into a glass jar and mixed with the  commercially available insulin solution. The resulting cloudy Suspension is sonicated directly with a titanium tip (approx. 5 W, 3 × 5 seconds at 22 ° C with 60 seconds each Time interval). The resulting, optically clear suspension contains vesicles with an average radius of 114 ± 17 nm.

Application and effect

The results are identical with the measurement accuracy those listed in Example 3.

Example 5 composition

143 mg soybean phosphatidylcholine
18 mg egg phosphatidylglycerol (98%)
20.5 mg sodium oleate
2 ml Actrapid HM 100 (200 IU)

Manufacturing

The lipids are in a glass vessel in 0.15 ml abs. Ethanol dissolved and mixed with the commercially available insulin solution. Otherwise the procedure is as in Example 4.

Application and effect

A fine plastic tissue is attached to the subject's forearm skin over an area of approx. 5 cm ² . This is then coated with 350 μl of the insulin-containing transfersome suspension and left open.

The drop in blood glucose level is 7.8 after 4 hours mg / dl and after 6 hours 8.5 mg / dl. It is therefore comparable that achieved in Example 3.

Example 6

The procedure is initially as in Example 3, but the Addition of saline is omitted; the cloudy, untreated liposome suspension is divided into two. 50% of Total volumes are sterile filtered; the rest turn 15 Sonicated for 5 seconds at room temperature. Of the mean vesicle diameter in both halves is similar, 300 nm or 240 nm.

Example 7

The procedure is as in Examples 3 and 5. Become liposomes however, filtered once, twice, or three times in succession. The mean diameters are 300, 240 and 200 nm.

The transferomes according to Examples 6 and 7 can be used apply comparable result according to example 3.

Example 8 composition

144.9; 152 mg soybean phosphatidylcholine
24.8; 17.6 mg deoxycholate, Na salt
1.45; 1.55 ml Actrapid HM 100 (145 IU)
0.16 ml ethanol, absolute

Manufacturing

The lipids are weighed into glass vessels and dissolved in ethanol and mixed with the insulin solution. The resulting cloudy Suspension is aged overnight and then after 12 Hours through a 0.22 micron filter. The nominal insulin concentration is 83 or 84 I.U. Der mean vesicle radius is 112 nm in both cases.

Application and effect

The general test conditions are as in the examples 1-4. The liposome suspensions (0.36 ml, equivalent to 30 I.U.) are applied to the inside of each arm; the Blood samples are taken from the other arm through a permanent cannula taken.

The results are shown in Fig. 5. They show that the preparation with a comparatively high surfactant content (sample 1, L / T = 3/1) can only bring about a hardly significant reduction in the blood glucose level; the almost optimal transfersomes, on the other hand, with a 30% lower relative surfactant content of L / T = 4.5 / 1, produce a very pronounced "hypoglycemia" that lasts for many hours.

This is further proof that the Transferomes the Active ingredient according to a completely different, new active principle through Wear skin as classic formulations.

This example further shows that in the examined here System can also be used such surfactant levels that from Are optimally distant, but particularly advantageous Results are achieved when the surfactant content is determined and  is chosen of a maximum elasticity and thus Permeability of the transferomes with simultaneous (still) sufficient stability against dissolution, bursting, Material loss etc. results.

Additional details on the Finding this optimum with different carrier systems in the one filed by the same applicant on the same filing date, already mentioned German patent application entitled "Preparation for drug application in the smallest droplet form".

Claims (16)

1. Preparation for the non-invasive administration of antidiabetic active substances, especially insulin, in the form of liposome-like droplets containing the active substance from a hydrophilic liquid enclosed in a membrane-like shell made of amphiphilic substance, characterized in that the membrane-like shell of amphiphilic substance containing at least one edge-active substance is formed, the content of edge-active substance between 0.1 and 99 mol%, in particular between 1 and 80 mol%, preferably between 10 and 60 mol% and particularly preferably between 20 and 50 mol% of the content of marginally active substance at which the solubilization point of the droplets is reached. 2. Preparation according to claim 1, characterized in that the edge tension of the Droplets up to about 10 piconewtons and / or regularly more than 50%, often more than 90% who do not active substance molecules applied invasively into the Get inside the body. 3. Preparation according to one of claims 1 or 2, characterized in that the Membrane structure a Is double layer. 4. Preparation according to claim 3, characterized in that the amphiphilic substance Lipid or lipoid of biological origin or a is a corresponding synthetic lipid, or a Modification of such lipids, especially a glyceride, Glycerophospholipid, isoprenoid lipid, sphingolipid, Steroid, sterol or sterol, a sulfur or carbohydrate-containing lipid, or another lipid, that forms stable double layers, preferably one semi-protonated fluid fatty acid. 5. Preparation according to claim 3 or 4, characterized in that the amphiphilic substance is a phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol,
a phosphatidic acid, a phosphatidylserine, a sphingomyelin or sphingophospholipid,
Glycosphingolipid (e.g. cerebroside, ceramide polyhexoside, sulfatide, sphingoplasmic malogen),
Ganglioside or other glycolipid
includes. 6. Preparation according to claim 3 or 4, characterized in that the amphiphilic substance synthetic lipid, preferably a dioleoyl, Dilinoleyl, Dilinolenyl, Dilinolenoyl, Diarachidoyl,  Dimyristoyl-, Dipalmitoyl-, Distearoyl, phospholipid or corresponding sphingosine derivative, glycolipid or other Diacyl or dialkyl lipid comprises. 7. Preparation according to one of claims 1 to 6, characterized in that there are several edge active Includes substances. 8. Preparation according to one of claims 1 to 7, characterized in that the edge-active substance comprises a nonionic, a zwitterionic, an anionic or a cationic surfactant, in particular
a long chain fatty acid or a long chain fatty alcohol,
an alkyl-trimethyl-ammonium salt, alkyl sulfate salt, cholate, deoxycholate,
Glycodeoxycholate, taurodeoxycholate salt, dodecyl dimethylamine oxide,
Decanoyl- or dodecanoyl-N-methylglucamide,
N-dodecyl-N, N-dimethylglycine, 3- (hexadecyldimethylammonio) propane sulfonate,
N-hexadecyl sulfobetaine, non-ethylene glycol octylphenyl ether, non-ethylene dodecyl ether,
Octaethylene glycol isotridecyl ether, octaethylene dodecyl ether,
Polyethylene glycol 20 sorbitan monolaurate,
Polyethylene glycol 20 sorbitan monooleate,
Polyhydroxyethylene cetyl stearyl ether, polyhydroxyethylene 4-lauryl ether, polyhydroxyethylene 23 lauryl ether,
Polyhydroxyethylene 8 stearate, polyhydroxyethylene 40 stearate,
Polyhydroxyethylene 100 stearate, polyethoxylated castor oil 40,
polyethoxylated hydrogenated castor oil, sorbitan monolaurate,
particularly preferably decanoyl- or dodecanoyl-N-methylglucamide,
Lauryl or oleoyl sulfate salts, sodium deoxycholate, sodium glycodeoxycholate,
Sodium oleate, sodium elaidate, sodium linoleate, sodium laurate, non-ethylene-dodecyl ether,
Polyethylene glycol 20 sorbitan monooleate (Tween 80),
Polyhydroxyethylene 23 lauryl ether, polyhydroxyethylene 40 stearate and / or
Sorbitan monolaurate and lysophospholipids such as
n-octadecylene (= oleoyl) -glycerophosphatidic acid, -phosphorylglycerol, or
-phosphorylserine, n-Dilauryk-glycerophosphatidic acid, -phosphorylglycerol, or
-phosphorylserine, n-tetradecyl-glycerophosphatidic acid, -phosphorylglycerol, or
-phosphorylserine and corresponding palmitoeloyl-, elaidoyl-, vaccenyl-lysophospholipids. 9. Preparation according to one of claims 1 to 8, characterized in that the total concentration amphiphilic substance in the preparation 0.1 to 30% by weight, preferably between 0.1 to 15% by weight, particularly is preferably 5-10% by weight. 10. Preparation according to one of claims 1 to 9, characterized in that it is the active ingredient 1 to 500 I.U insulin / ml, preferably between 20 and 100 I.U./ml contains and the concentration of the amphiphilic substance in the Preparation in the range of 0.1 to 20 wt .-%, in particular between 0.5 and 15% by weight, particularly preferably between 2.5 and 10 wt .-%. 11. Preparation according to one of claims 1 to 10, characterized in that it is an amphiphilic substance Phosphatidylcholine and / or Phosphatidylglykol and als edge active substance a lysophosphatidic acid or Lysophosphoglycerol, a deoxycholate, glycodeoxycholate or cholate salt, a laurate, myristate, oleate,  Palmitoleate, or corresponding phosphate or sulfate Salt, and / or a PGE sorbitan ester alkyl ether and as Contains active ingredient recombinant human insulin. 12. Preparation according to one of claims 1 to 11, characterized in that the vesicle radius of Preparation droplets between about 50 and about 200 nm, preferably between about 100 and about 180 nm. 13. Process for the preparation of a preparation for non-invasive administration of anti-diabetic Active ingredients in which one is amphiphilic from at least one Substance, at least one hydrophilic liquid and at least one anti-diabetic agent, in particular Insulin, liposome-like droplets, characterized in that the membrane-like shell the droplets of the amphiphilic substance and at least one edge-active substance generated, in particular by Stir in by evaporation from a reverse phase, by an injection or dialysis procedure, by mechanical stress such as shaking, stirring, Homogenize, sonicate, rub, freeze or Thawing or high or low pressure filtration.   14. The method according to claim 1, characterized in that the droplet formation by Filtration is effected and the filter material Pore size from 0.1 to 0.8 µm, especially 0.15 to 0.3 µm and particularly preferably 0.22 µm, several filters can be used in series. 15. The method according to any one of claims 13 or 14, characterized in that the active ingredient inclusion at least partially after droplet formation. 16. The method according to any one of claims 13 to 15, characterized in that the liposome-like Droplets from a concentrate just before use or lyophilisate.